Since their discovery in 1997 by Okamoto and colleagues TT viruses (TTV) have been found to be widely spread in all human populations, in domestic animals, and in old world primates (1,2). A large number of types and pseudotypes have been identified in humans, pointing to a remarkable heterogeneity of this virus family now being assigned as a new virus family, Anelloviridae (3). Viral DNA can be demonstrated in sera of almost every human being and some reports even document such DNA in newborn children and cord blood, suggesting prenatal transmission of these agents (4,5). In spite of the widespread occurrence of these viruses, intensive research performed during more than 10 years failed to demonstrate a pathogenic role of such infections in human disease.
TT viruses have not been successfully replicated in human tissue culture cells, although indications exist that replication can be achieved in human cells of epithelial or hematopoietic origin. In the latter, replicative cycles of herpes group viruses (Epstein-Barr virus) seem to exert an enhancing effect for the amplification of latent or transfected TTV genomes (6). In addition, TT viruses frequently reveal intramolecular rearrangements which lead to subviral DNA genomes in part defective and with novel open reading frames. They replicate autonomously over prolonged periods of time in infected tissues (7). These subviral DNAs are found in normal and malignant human biopsy materials.
During the past years, some data have been compiled indicative of an association of TT virus infection with human malignant tumors. A high rate of TT virus load has been noted in a spleen biopsy of a patient with Hodgkin's lymphoma (24 individual TTV genotypes) (8). Similarly, other reports describe a higher rate of TTV prevalence in colorectal and esophageal cancer and in hematopoietic malignancies in comparison to non-tumorous tissue from the same or other patients (9,10). Yet, the ubiquity of these infections rendered an interpretation of these results rather difficult and did not permit a linkage of these observations with tumor development.